Chemical conjugation of 2-hexadecynoic acid to C5-curcumin enhances its antibacterial activity against multi-drug resistant bacteria. Issue 22 (15th November 2015)

• Record Type: Journal Article
• Authors: Sanabria-Ríos, David J.; Rivera-Torres, Yaritza; Rosario, Joshua; Gutierrez, Ricardo; Torres-García, Yeireliz; Montano, Nashbly; Ortíz-Soto, Gabriela; Ríos-Olivares, Eddy; Rodríguez, José W.; Carballeira, Néstor M.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 22(2015)
• Page Start: 5067
• Page End: 5071
• Publication Date: 2015-11-15
• Subjects: C5-curcuminoids synthesis -- Antibacterial agents -- MRSA -- Antagonism -- DNA gyrase; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.10.022
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: The first total synthesis of a C5-curcumin–2-hexadecynoic acid (C5-Curc–2-HDA, 6 ) conjugate was successfully performed. Through a three-step synthetic route, conjugate6 was obtained in 13% overall yield and tested for antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) strains. Our results revealed that6 was active against eight MRSA strains at MICs that range between 31.3 and 62.5 μg/mL. It was found that the presence of 2-hexadecynoic acid (2-HDA, 4 ) in conjugate6 increased 4–8-fold its antibacterial activity against MRSA strains supporting our hypothesis that the chemical connection of4 to C5-curcumin (2 ) increases the antibacterial activity of2 against Gram-positive bacteria. Combinational index (CIn) values that range between 1.6 and 2.3 were obtained when eight MRSA strains were treated with an equimolar mixture of2 and4 . These results demonstrated that an antagonistic effect is taking place. Finally, it was investigated whether conjugate6 can affect the replication process of S. aureus, since this compound inhibited the supercoiling activity of the S. aureus DNA gyrase at minimum inhibitory concentrations (MIC) of 250 μg/mL (IC50 = 100.2 ± 13.9 μg/mL). Moreover, it was observed that the presence of4 in conjugate6 improves the anti-topoisomerase activity of2 towards S. aureus DNA gyrase, which is in agreement with results obtained from antibacterial susceptibility tests involving MRSA strains.